Diabetes is the fastest growing disease in the USA (mirroring increases in obesity rates) and is rising as a leading cause of death mostly from cardiovascular related pathologies. The current prevalence of diabetes is ~9% with a further ~30% as pre-diabetics. Estimated 2007 direct and indirect costs of diabetes in the USA are $174 billion. Compelling evidence has emerged implicating mitochondrial dysfunction in the pathophysiology of obesity, insulin resistance and type 2 diabetes. Insulin sensitizing agents used for the treatment of diabetes such as thiazoledinediones (TZDs) induce mitochondrial biogenesis and this may partly explain their therapeutic action. In spite of their therapeutic benefit they however, have the potential for serious side-effects. Flavonoids as TZDs have been reported to induce mitochondrial biogenesis favorably impacting cellular and organ bioenergetics. This class of natural compounds is in general, recognized as safe. However, their possible use as drugs for the treatment of pre-diabetes or diabetes has been poorly explored. Under this proposal, entitled "Targeting cellular bioenergetics for the treatment of pre-diabetes and diabetes: A team approach", we will create a highly integrated, multidisciplinary research team specifically assembled to systematically explore the prospect of the cacao flavanol (-)-epicatechin (and novel synthetic derivatives) to favorably affect cellular/organ bioenergetics. We intend to gather preliminary data to dispel the common notion that flavanols act mainly as antioxidans and that "the higher the dose, the greater the effect". Rather, we intend to generate evidence pertaining to their effect on specific cell receptors acting within specific dose-response profiles. During this initial seed period, we will fully assemble and integrate a unique and highly-experienced team consisting of basic scientists (molecular and organ physiologists) and translational experts to systematically examine the promise of epicatechin and novel derivatives as agents for the treatment of pre-diabetes and diabetes.